PSOC Penn Liver Cancer: pre-Malignant Stiffening, Membrane Transduction, & Nuclear Rheology, The Transdisciplinary nature of Cancer Physics requires efficient and effective interactions across multiple boundaries. We have chosen to focus on primary liver cancer, predominantly hepatocellular carcinoma (HCC), which are highly morbid tumors that represent the third most common cause of cancer death worldwide. HCC almost always arises in the setting of end-stage liver fibrosis, termed cirrhosis, and new in situ methods of measuring liver stiffness are emerging as effective predictors of the relative risk of HCC. Patients with stiffer livers demonstrate dramatically increased rates of HCC, but clinical acceptance will no doubt be helped by - or even require - studies proposed here. We seek to determine the nature of the relationships between human HCC with fresh primary samples and the mechanics of liver tissues, the signals to cells, and the roles of nuclear mechanics in DNA stability and tumor growth. Five clinicians at Penn who regularly see patients or samples with liver disease and liver cancer are involved in the proposed PSOC Penn, and so the opportunities to impact the Clinic are tangible. In formulating this cross-cutting proposal with 3 Research Projects and 2 Cores, we propose a Multi-PI Leadership Plan to best represent the diverse areas of expertise and responsibility: Dennis Discher PhD (Prof. Eng'g Appl Sci, Grad Groups Physics, Cell & Molec Biol) Contact PI, Admin Core Lead, PI of Project-3 Nuclear Rheology: Cancer Cell line Expertise. Paul Janmey PhD (Prof. Physiology, Physics, and Bioengineering) PI of Project-1 Liver Mechanics: Cancer Cell line Expertise. Rebecca Wells MD (Assoc. Prof. Medicine, Pathology, and Laboratory Medicine) PI of Core-1 Liver Cancer Tissue and Models: Expertise in Mechanisms of Liver Disease. David E. Kaplan MD (Asst. Professor of Medicine, and Director of Hepatology) Co-PI of Core-1 Liver Cancer Tissue and Models: Clinical Expertise in Liver Cancer. Andrea Liu PhD (Prof. Physics and Chemistry) PI of Core-2 Theory: Expertise in Statistical Physics Modeling. Penn is a single, integrated Campus, with all of the labs involved in the Center walkable within 5-10 minutes, and Penn's Medical Center Hospital serves the greater Philadelphia area with one of the larger liver disease centers in the country. To integrate the proposed PSOC Penn within the University's broad and deep efforts in Cancer, all leaders and faculty members of the PSOC will become members of Penn's Abramson Cancer Center (if they are not already). The Director of the Abramson Cancer Center, Prof. Chi Van Dang, will be PI of Pilot Project-1 and will be a key member of the Center Advisory Committee. More broadly, the PSOC Penn will support through Education & Outreach a wide variety of programs that aim to build a vibrant community of students and fellows who embody the multidisciplinary approach to understanding the physics of cancer with an aim of transforming the next generation of scientists, engineers and clinicians.